Coordination of cell cycle progression and mitotic spindle assembly involves histone H3 lysine 4 methylation by set1/COMPASS

Traude H. Beilharz, Paul F. Harrison, Douglas Maya Miles, Michael Ming See, Uyen Minh Merry Le, Ming Kalanon, Melissa Jane Curtis, Qambar Hasan, Julie Saksouk, Thanasis Margaritis, Frank Holstege, Vincent Geli, Bernhard Dichtl

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Methylation of histone H3 lysine 4 (H3K4) by Set1 complex/COMPASS is a hallmark of eukaryotic chromatin, but it remains poorly understood how this post-translational modification contributes to the regulation of biological processes like the cell cycle. Here, we report a H3K4 methylation-dependent pathway in Saccharomyces cerevisiae that governs toxicity toward benomyl, a microtubule destabilizing drug. Benomyl-sensitive growth of wild-type cells required mono- and dimethylation of H3K4 and Pho23, a PHD-containing subunit of the Rpd3L complex. Δset1 and Δpho23 deletions suppressed defects associated with ipl1-2 aurora kinase mutant, an integral component of the spindle assembly checkpoint during mitosis. Benomyl resistance of Δset1 strains was accompanied by deregulation of all four tubulin genes and the phenotype was suppressed by tub2-423 and Δtub3 mutations, establishing a genetic link between H3K4 methylation and microtubule function. Most interestingly, sine wave fitting and clustering of transcript abundance time series in synchronized cells revealed a requirement for Set1 for proper cell-cycle-dependent gene expression and Δset1 cells displayed delayed entry into S phase. Disruption of G1/S regulation in Δmbp1 and Δswi4 transcription factor mutants duplicated both benomyl resistance and suppression of ipl1-2 as was observed with Δset1. Taken together our results support a role for H3K4 methylation in the coordination of cell-cycle progression and proper assembly of the mitotic spindle during mitosis.

Original languageEnglish
Pages (from-to)185-199
Number of pages15
JournalGenetics
Volume205
Issue number1
DOIs
Publication statusPublished - 1 Jan 2017

Keywords

  • Aurora kinase
  • Benomyl
  • Cell cycle
  • Gene expression
  • Histone methylation

Cite this

Beilharz, Traude H. ; Harrison, Paul F. ; Miles, Douglas Maya ; See, Michael Ming ; Le, Uyen Minh Merry ; Kalanon, Ming ; Curtis, Melissa Jane ; Hasan, Qambar ; Saksouk, Julie ; Margaritis, Thanasis ; Holstege, Frank ; Geli, Vincent ; Dichtl, Bernhard. / Coordination of cell cycle progression and mitotic spindle assembly involves histone H3 lysine 4 methylation by set1/COMPASS. In: Genetics. 2017 ; Vol. 205, No. 1. pp. 185-199.
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abstract = "Methylation of histone H3 lysine 4 (H3K4) by Set1 complex/COMPASS is a hallmark of eukaryotic chromatin, but it remains poorly understood how this post-translational modification contributes to the regulation of biological processes like the cell cycle. Here, we report a H3K4 methylation-dependent pathway in Saccharomyces cerevisiae that governs toxicity toward benomyl, a microtubule destabilizing drug. Benomyl-sensitive growth of wild-type cells required mono- and dimethylation of H3K4 and Pho23, a PHD-containing subunit of the Rpd3L complex. Δset1 and Δpho23 deletions suppressed defects associated with ipl1-2 aurora kinase mutant, an integral component of the spindle assembly checkpoint during mitosis. Benomyl resistance of Δset1 strains was accompanied by deregulation of all four tubulin genes and the phenotype was suppressed by tub2-423 and Δtub3 mutations, establishing a genetic link between H3K4 methylation and microtubule function. Most interestingly, sine wave fitting and clustering of transcript abundance time series in synchronized cells revealed a requirement for Set1 for proper cell-cycle-dependent gene expression and Δset1 cells displayed delayed entry into S phase. Disruption of G1/S regulation in Δmbp1 and Δswi4 transcription factor mutants duplicated both benomyl resistance and suppression of ipl1-2 as was observed with Δset1. Taken together our results support a role for H3K4 methylation in the coordination of cell-cycle progression and proper assembly of the mitotic spindle during mitosis.",
keywords = "Aurora kinase, Benomyl, Cell cycle, Gene expression, Histone methylation",
author = "Beilharz, {Traude H.} and Harrison, {Paul F.} and Miles, {Douglas Maya} and See, {Michael Ming} and Le, {Uyen Minh Merry} and Ming Kalanon and Curtis, {Melissa Jane} and Qambar Hasan and Julie Saksouk and Thanasis Margaritis and Frank Holstege and Vincent Geli and Bernhard Dichtl",
year = "2017",
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Beilharz, TH, Harrison, PF, Miles, DM, See, MM, Le, UMM, Kalanon, M, Curtis, MJ, Hasan, Q, Saksouk, J, Margaritis, T, Holstege, F, Geli, V & Dichtl, B 2017, 'Coordination of cell cycle progression and mitotic spindle assembly involves histone H3 lysine 4 methylation by set1/COMPASS', Genetics, vol. 205, no. 1, pp. 185-199. https://doi.org/10.1534/genetics.116.194852

Coordination of cell cycle progression and mitotic spindle assembly involves histone H3 lysine 4 methylation by set1/COMPASS. / Beilharz, Traude H.; Harrison, Paul F.; Miles, Douglas Maya; See, Michael Ming; Le, Uyen Minh Merry; Kalanon, Ming; Curtis, Melissa Jane; Hasan, Qambar; Saksouk, Julie; Margaritis, Thanasis ; Holstege, Frank; Geli, Vincent; Dichtl, Bernhard.

In: Genetics, Vol. 205, No. 1, 01.01.2017, p. 185-199.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Miles, Douglas Maya

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AU - Curtis, Melissa Jane

AU - Hasan, Qambar

AU - Saksouk, Julie

AU - Margaritis, Thanasis

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AU - Geli, Vincent

AU - Dichtl, Bernhard

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